Susceptibility to Tuberculosis 1 (sst1): Novel Target for Diagnosis and Treatment of Mycobacterium tuberculosis
Summary Background: Tuberculosis is the seventh most important cause of global premature mortality and disability. Currently there are 8 million new cases and 3 million deaths annually from tuberculosis, and it is projected that a total of 225 million new cases and 79 million deaths will occur between now and 2030. Despite the prevalence and incidence of tuberculosis, host populations are heterogeneous in terms of their susceptibility to infection, and only 10% of the individuals infected with TB actually develop tuberculosis. Epidemiological, clinical, and experimental approaches have convincingly demonstrated that host resistance to infection with intracellular pathogens is significantly influenced by genetic polymorphisms. However, the effect of these genes is accountable for only a small proportion of the overall genetic variation, justifying the need for multiple approaches for identifying additional host resistance factors.
Invention: The identification of a novel gene, sst1, required for intracellular pathogen resistance to Mycobacterium tuberculosis. The survival time of sst1 resistant (sst1R) congenic mice infected either intravenously (i.v.) with a high dose of MTB, or with a low dose of MTB via a respiratory route is significantly lengthened relative to sst1 sensitive (sst1S) counterparts. The specific effect of the sst1 locus in progression of tuberculosis was related to more efficient control of MTB multiplication primarily in the lungs. sst1S mice also developed encapsulated necrotic lung lesions after exposure to a low dose aerosol whereas the sst1R mice did not.
Applications Applications: A novel target for the discovery of agents that prevent or downregulate sst1 gene expression for the treatment of Mycobacterium tuberculosis or L. monocytogenes infection. The agents are to be designed for individuals that innately lack expression of the Ipr1 homologue as well as patients that lose expression as the result of having been chronically infected with the pathogen. The invention also encompasses a method for determining a patientâ€™s susceptibility to infection by monitoring expression of sst1. A positive gene expression indicates that the individual has innate resistance to infection by cytosolic pathogens, while negative gene expression indicates the patient is highly susceptible to infection. One can also screen for mutations in the sst1 gene by DNA sequence analysis and immunohistochemical methods.
Publications: Ipr1 gene mediates innate immunity to tuberculosis. Nature Vol. 434, 7 April 2005
Genetic architecture of tuberculosis resistance in a mouse model of infection. Genes and Immunity (2006) 7, 201â€“210.
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